In the pharmaceutical industry it is strongly desired to develop containers of polymeric materials to replace traditional glass containers in order to provide less resource consuming, cheaper and more convenient packaging systems. It is, however, a considerable technical problem to develop safe and cheap containers made of polymeric material which can replace glass as a barrier forming material against the environment and be compatible with a variety of fluids including lipophilic fat emulsions for parenteral nutrition. There have been many attempts to introduce polymeric materials for such lipophilic agents, but problems with degradation from penetrating oxygen and migration of components from the polymeric material into the stored fluids, especially after sterilization with steam at autoclaving conditions have prevented a wide-spread commercial use.
A highly sophisticated container for long-time storage of fluids aimed for parenteral administration is disclosed in the Swedish patent application SE 9601348-7. By a careful selection of polymeric materials, this type of container is capable of withstanding steam sterilization when finally filled and assembled and yet form a suitable barrier against environmental oxygen to protect oxygen degradation sensitive components during storage without involving any material that is incompatible with lipids. This container consists of an inner container, having one or several compartments for storage of drugs which readily can be mixed, just prior to the administration, enclosed in a substantially airtight outer envelope. In the space between the inner container and the envelope, an oxygen scavenging composition is placed to consume residual oxygen and the small amounts of oxygen penetrating through the envelope. To improve on the safety of the product, an oxygen indicator can be placed between the envelope and the inner container through which the transparent envelope visually indicates an oxygen leakage by a change in color. Especially for such oxygen sensitive products like parenteral nutrients comprising polyunsaturated fatty acids and certain amino acids, there is a demand to have simple and reliable indication of the integrity of the products, since many of the patients dependent on such a therapy are confined to self-administration in their homes with a supply of containers.
The demands of an oxygen indicator for a medical container for parenteral nutrients are equally high as the other features of the container. It must be capable to withstand autoclavation procedures (steam sterilization at about 121.degree. C. for a prescribed time period, usually about 19 to 20 minutes) without losing its characteristics. It must consist of safe and non-toxic components which have a negligible tendency to migrate and waste the stored products and it must be fully compatible with the remaining parts of the container. The indicator function must be suitably sensitive and reliable so a distinct change in color visualizes a predetermined exposure to oxygen and thus the potential waste of the product which then must be discarded. In addition, a functional oxygen indicator should be cheap and easy to produce and assemble with the package.
Conventional visual oxygen indicators known to the art used in the form of tablets inside packages for pharmaceuticals or certain food products, such as Ageless-Eye KS from Mitsubishi based on methylene blue as a coloring agent, will not be able to withstand autoclavation. After autoclavation, the color change will be less distinct and instead of a homogenous blue color, a patchy or stained blue to pink colors will appear that severely impairs the sensitivity of their oxygen indicating capacity. This type of indicator is also normally recommended with a limited shelf-life of six months.
Oxygen indicators agents may also be possible to disperse in the polymeric packaging material, as suggested in the International patent application WO 95/29394 to W.R. Grace & Co. This material have a drawback in that its riboflavin indicator component is sensitive to heat and will not withstand autoclavation with maintained capacity. It would also be wasted by high temperature welding processes of the packaging material. Obviously, there still is a desire for improvements related to oxygen indicators. Especially to find reliable, cheap, non-migrating visual oxygen indicators to be included in container systems storing oxygen sensitive parenteral drugs intended to be steam sterilized after their final assembly.
The present invention aims to provide new color compositions suitable to be comprised in an oxygen indicator as well as being incorporated in water based surface treatment compositions.
It is an object of the present invention to provide improved oxygen indicators based on said colored compositions which are especially suitable to be a part of a container for long-time storage of oxygen sensitive pharmaceuticals for parenteral administration.
Another object of the present invention is to provide an oxygen indicator which can withstand autoclavation without losing any important characteristics and which has suitable characteristics for being assembled with a container for storing oxygen sensitive pharmaceuticals.
A further object of the present invention is to provide an oxygen indicator which is composed of constituents with less potential toxicity and thereby being especially suitable for the pharmaceutical and the food industry.
A still further object of the invention is to provide an oxygen indicator with high reliability which may serve as guarantee that patients dependent on parenteral nutrition not will infuse accidentally oxidized solutions.
The present invention relates to a color composition comprising an agent containing pyrogallol entities, and an iron (II) salt and an acid.
The salts of iron (II) useful in the present invention must be readily soluble to avoid the formation of precipitations of poorly soluble complexes with other components of the color composition. Preferably, the iron(II) salts are selected from a group consisting of iron(II)sulfates, iron(II)acetate, iron(II)nitrate, iron(II)chloride and iron(II)trifluoroacetate.
The agent containing pyrogallol entities are capable of complex binding iron(III), thus forming a colored product. It may consist of pyrogallol derivatives preferably gallic acid and its derivatives, particularly various esters of gallic acid. However, pure pyrogallol or gallic acid (which is carboxylated pyrogallol) can also be used, in particular when the toxicity of pyrogallol can be controlled or is of limited importance. A suitable agent is tannin of natural, synthetic or semi-synthetic origin comprising ester bridges in a network between a plurality of gallic acid entities.
The acid component is preferably selected to avoid the formation of poorly soluble complexes with iron ions and it should not be so strong that it hydrolyses the agent having gallic acid entities to free gallic acid which should be avoided since it may modify the predicted color characteristics of the composition. Preferably, an organic acid having at least two carboxylic groups is selected for the color composition and most preferably an organic acid having general formula HOOC--(CR.sub.1 R.sub.2).sub.n --COOH, wherein n=1-4, R.sub.1 is hydrogen or a hydroxyl radical, and R.sub.2 is hydrogen or a carboxyl radical. In order to obtain a reversible color reaction, an alpha-hydroxy acid having at least two carboxylic groups, such as citric acid is suitable as the acid component in the color compositions.
From this information, it is possible to select alternative functioning iron(II) salts and acids of suitable strength for the color composition. However, the most preferred color composition according to the present invention comprises iron(II) sulphate or iron(II) sulphate heptahydrate as an iron(II) salt and citric acid or citric acid 1-hydrate, as an acid. Especially suitable color composition comprises (A) iron(II)sulphate or iron(II)sulphate heptahydrate, (B) a tannin as the pyrogallol entity containing agent and(C) citric acid or citric acid 1-hydrate optionally in combination with an appropriate carrier agent. The weights of the components (A), (B) and (C) in the inventive composition preferably have the following relationships; (A):(B) is between 4:1 and 1:2 and (C):(B) is between 6:1 and 1:1. The carrier agent is suitably a cold swelling starch and preferably propyleneoxide ether of starch which gives the composition a certain viscosity and acts as a filling agent. Also other conventional thickeners, such as carboxymethyl cellulose (CMC), and diluents giving the composition a desired viscosity or adhesion, are conceivable to introduce in the compositions both as complements and substitutes to the starch.
When being exposed to environmental air, a preferred color composition will change color after a certain time. In the originally pale yellow composition, the iron(II)sulphate is oxidized in air to iron(III) which reacts with the aromatic system of the tannin, resulting in a change of color to black from the formed complexes between iron(III) and tannin. Originally, the composition will have a pale yellow color basically derived from the tannin. When exposed to oxygen, the iron will be oxidized to iron(III) which starts to react with the aromatic system of tannin molecules and a resulting green color and subsequently black color will appear. An important characteristic of the inventive color composition, is its color reaction reversibility. The system can be reversed in an oxygen free atmosphere back to its original pale yellow color by subsequent reduction of iron ions.
The mechanism behind the color reaction can be explained with that the gallic acid entities of the tannin is capable forming relatively stable pyrogallol anions which either may form a black complex with Fe(III), or react with oxygen to form a radical. The radical pyrogallol entity can also react with Fe(II) to form the black complex.
By varying the amounts of citric acid, the time to the color change can be controlled. In a colored composition comprising a water solution of 2% FeSO4, 1.3% tannin and 3.5% citric acid, a color change is observed after about 4 hours. Increasing amounts of citric acid will substantially prolong the time to the color change by delaying the oxidation of Fe(II) to Fe(III). The system may also be controlled by varying the amount of tannin, since higher amounts of this constituent gives darker colors. An increase in the amounts of tannin and Fe (II), respectively, in an indicator composition will shorten the time to a color change to the final black color.
The inventive color composition has a sensitivity to environmental oxygen which makes it highly suitable for the use as an oxygen indicating composition, while its aesthetic appearance and conservative capacity gives it a high potential as a main ingredient in water-based surface treatment agents.
An especially preferred embodiment of the present invention refers to an oxygen indicator comprising the above mentioned compositions. The indicators are suitable to determine if the level of oxygen penetrating into a controlled oxygen depleted atmosphere is high enough to provide a color change of the indicator. Oxygen indicators according to the present invention consist of the mentioned color compositions optionally combined with a carrier.
The carrier is preferably an enclosing package formed membrane made of a polymeric material through which oxygen can permeate, but also impregnated strips of a porous material and hydrogels are conceivable alternatives as carriers. Alternatively, the oxygen indicator can be formulated as a tablet, in the form of pellets, formulated in a hydrogel or compounded into various solid or semi-solid carries generally known to persons skilled in this technique. For example, the oxygen indicating colored composition can be mixed with a suitable carrier composition which is conventionally used in tabletting or pelletization procedures. Another alternative is to include the indicator in a layer in a multilayered polymeric material prepared by lamination or coextrusion. The indicator composition may then be dispersed and evenly distributed in a melted polymer material which is formed into layer in multilayered polymeric film structure suitable for the manufacturing of containers with conventional technology.
Especially in applications related to the pharmaceutical industry, the oxygen indicators based on the colored composition, must be possible to steam sterilize in an autoclavation process and be compatible with the other components of a container filled with pharmaceuticals. For this reason, the carrier should also be capable of such a heat treatment and it is suitable to enclose the indicator composition in a small sachet or bag of a similar material as the container containing the degradable pharmaceuticals with which it is aimed to be stored. To enable a correct indicator function it is a prerequisite that the material enclosing the indicator admits oxygen transport. Preferred materials are based on polyolefins and may comprise thermoplastic elastomers to improve on their mechanical properties. Especially suitable are materials based on polyethylene and/or polypropylene and their copolymers. An especially preferred material typically will consist of a multilayered structure and contain a high amount of polypropylene. An example of such a material is Excel.RTM. from McGaw Inc. which is described in the European patent specification 0 228 819 and also in the mentioned Swedish patent application SE 9601348-7.
The described indicators according to the present invention have unexpected resistance against heat treatments and will maintain intact oxygen indicating capacity even if treated by sterilizing steam at 121.degree. C. for more than 19 to 20 minutes and has been demonstrated to withstand such conditions for at least 60 minutes.
It has been noted that certain color compositions according to the present invention are light sensitive and may change color spontaneously if stored in intense light, including daylight, irrespectively of the oxygen exposure. This reaction is believed to originate from the ability of the organic acid (citric acid) to complex to Fe(III) ions and reduce said ions to Fe(II), in the presence of light. In this process, the citric acid entity will rearrange and split off carbon dioxide to eventually form acetone. However, if the indicator has reached the stage of an essentially black color, the black precipitates thus formed will not be possible to reverse and the color will remain black, irrespective of the light conditions. If, on the other hand, the indicator only has reached the green color state, this color can be reversed to the original pale yellow color if a sufficient amount of light is present. For these reasons, it may be suitable to enclose the inventive oxygen indicator color which are sensitive or suspected to be sensitive for light in a package which has been made light absorbing or light shielding to protect the composition from light of frequencies of a color affecting influence. The enclosing packages can thus be provided with a light protecting film or coating which has a capacity of removing the affecting light. Such films or other materials which can act as a filter for daylight or for UV-radiation are well known to persons skilled in the art and will not be discussed in more detail. Alternatively, for compositions having only a moderate or low light sensitivity, packages containing indicators based on the compositions, can be provided with instructions for storage in darkness.
An especially preferred colored composition for an indicator according to the present invention will comprise between 1 to 4 g of iron(II)sulphate or its heptahydrate, between 0.5 to 4 g of tannin, between 1 to 10 g of citric acid or citric acid I -hydrate, and optionally between 2 and 15 g of a filling material, suitably propyleneoxide ether of starch and water up to 100 g. The filling material should be regarded as optional. The colored compositions are preferably enclosed in bags of Excel.RTM. having a size of about 0.5 to 2 ml. Specific examples of functioning indicator compositions are disclosed in the following detailed description of the invention. However, the skilled person will both be able to depart from these given frames and find especially suitable levels within them and yet fall within the scope of the present invention set out by the appended claims.
An oxygen indicator according to the present invention is prepared by mixing predetermined amounts of the iron(II) salt, the tannin and the acid to a homogenous composition. The resulting mixture is dissolved in water. This procedure preferably takes place in a controlled, substantially oxygen-free nitrogen gas atmosphere. The mixture is filled into bag shaped containers of Excel.RTM. or a comparable material which are sealed by means of welding in the controlled atmosphere. The indicators are stored in an oxygen-free atmosphere until they are assembled with the other parts of medical container. These indicators are especially suitable in transparent flexible containers of the type described in the mentioned Swedish patent application SE 9601348-7 (Pharmacia AB), consisting of an inner container with fluids for parenteral administration enclosed in an outer transparent air-tight envelope. When assembling this type of containers, an oxygen indicator and an oxygen scavenger are placed together with the fluid filled inner container in an enclosing envelope in an oxygen-free or oxygen depleted controlled atmosphere, whereupon the envelope is finally sealed. The container can now be sterilized in its final condition before storage.
During a normal storage, the small amounts of oxygen remaining in the container and in the stored products and such oxygen diffusing through the envelope will be consumed by the oxygen scavenger and not be able to deteriorate the stored products or affect the indicator. However, if the container is erroneously assembled or accidentally damaged so environmental oxygen is leaking into it in a sufficiently large amount, the oxygen scavenger will be saturated and the surplus oxygen will react with the components of the indicator which will change color from pale yellow to green and after certain time to black. The skilled person will be able to make estimations about the time to change the color of the indicator and what level of oxygen is required for the change and predict how it will affect the oxygen labile stored products.
As discussed above, there is also a possibility to control the time to the color change by selecting different levels of the components of the indicator. It is also possible to adjust the reactivity of the indicator by selecting a higher surface to volume ratio of the enclosing package for the color composition compared to the container filled with the oxygen sensitive material. By a selection of such appropriate dimensional parameters, an obvious color change of the indicator can be obtained before the stored material is adversely affected by the oxygen. The manufacturer of container systems for the oxygen sensitive products thereby readily can provide them with suitable instructions for the user, by considering the indicator characteristics and the oxygen sensitivity of the products. For many practical applications, such as storing sensitive parenteral nutrients containing polyunsaturated fatty acids or amino acids, a prescribed color change of the indicator will be a clear indication for the user to discard the container.
Since the inventive indicators are not deteriorated in their capacity of visually indicating oxygen after conventional autoclavation procedures, they are especially advantageous to use in connection with storage packages of pharmaceutical products for parenteral use. Furthermore, they only contain components which have low or negligible tendency to migrate through polymeric materials frequently selected in medical containers like Excel.RTM. and other polypropylene containing multilayer films. The indicators contain only components which have a low toxicity and are cheap and simple to produce and they will consist of a color composition enclosed in small package of polymeric material which can be selected to be entirely compatible with materials of the medical container.
A further highly advantageous property of the inventive oxygen indicators is that they can be based on a color composition having a reversible color reaction. A storage in an oxygen-free environment can lead to that the reaction behind the color change is reversed if light is present, so a greenish indicator can be changed back to its initial pale yellow color after reduction of the iron(II) ions. A fully developed black indicator will however, not be reversed to its original yellow color. An important consequence of the reversibility of the color reaction is that the environment need not to be entirely or substantially oxygen-free when finally assembling the container comprising filled inner primary container, oxygen scavenger and oxygen indicator enclosed in the outer airtight envelope for storing oxygen sensitive products.
It is therefore possible to manufacture a container from an inner container made of a material which is at least partially penetrable for oxygen which is filled with the oxygen sensitive material and sealed under controlled circumstances, for example by means of inert gas. The inner container can be assembled in an atmosphere having normal, ambient oxygen level with an oxygen indicator according to the present invention and an oxygen absorber in an airtight, sealable, transparent envelope of a polymeric material, so as to form a final sealed container. The container will as a final step undergo sterilization by means of steam at 121.degree. C. for at least 15 minutes (autoclavation) and preferably for about 19 to 20 minutes. Appropriate materials for the inner container, the outer envelope and the oxygen scavenger composition are disclosed in more detail in the Swedish patent application 9601348-7.
Briefly, the inner container is multilayered and made of polyolefins, such as polyethylenes or polypropylenes--as well as suitable homopolymers and copolymers--that are chemically inert to the stored fluid, autoclavable, weldable, flexible, with a high melting point, and possibly recyclable. One such suitable multilayer material is Excel.RTM..
The outer envelope also is multilayered, with an outer layer preferably made of a metal oxide (such as an oxide of silicon and/or aluminum and/or titanium) together with at least one polymeric material (such as polyethylene terephthalate or PET), and a complex inner layer of EVOH (polyethylene-vinyl alcohol) and polypropylene (PP) assembled as: PET-glass/glue/PP/tielayer/EVOH/tielayer/PP, where "glass" refers to a metal oxide layer. A commercially available product of similar composition (Oxnil.RTM.) is suitable for this purpose.
It is of a great advantage for simplifying the manufacturing process that the final assembly and sealing of the container for storage can be performed in an atmosphere of normal, ambient composition, however controlled from microbial contamination, without any laborious and expensive equipment for atmosphere control. For stored agents normally used in parenteral nutrition like lipid emulsions and amino acid solutions, the production of final container can be performed in an ambient atmosphere during a limited time period estimated to about 1 to 2 hours, when using indicators preferred according to the present invention and other materials as disclosed above. For other stored agents and other materials selected for the parts of the final container, it is possible to make estimations about the oxygen demand and arrive with safe instructions for the production of containers. The indicator reactivity can be modified, as disclosed above, to be adapted to various situations and levels oxygen exposure during its assembly with the container.
Besides being suitable as an indicator composition, the inventive color composition has good characteristics as a surface treatment composition, especially for articles of rough or untreated wood and iron. Since iron(II) in the presence of environmental oxygen will oxidize to iron(III), a composition with tannin and starch will form a difficult to dissolve black or blackish gray product. The presence of citric acid and iron sulphate will contribute to conserve the product from microbial degradation during storage. By the addition of another pigment, such as madder lake, a suitable for example an excellent red, surface treatment composition for outdoor use on wood can be obtained. In addition to its contribution to the color, the iron(II)sulphate will also serve as a powerful fungicide. A surface treatment composition according to the present invention will be advantageous over commercially available starch based composition for wood treatment, such as Falu Rodfarg, by its improved adhesiveness which will be especially apparent if up to 10% (w/w) of linseed oil is added.
Color compositions according to the present invention will also be advantageous for surface treatment of iron products whenever it is desired to give them a blackish finish. The inventive color composition can simply be applied to the iron articles and dried whereupon an anti-corrosive black surface is obtained from the insoluble black complexes between iron and tannin. In order to obtain an excellently applicable iron surface treatment composition, up to 10% (w/w) of linseed oil can be added to the color composition.
In Example 11 below, a composition suitable as a base for surface treatment composition is disclosed which shall be regarded as a non-limiting illustration to the capacity of inventive compositions of being used in applications for protective and decorative coating of various articles.